Alternative macrophage activation limits immunopathology Macrophages (MF) form a heterogeneous population of mononuclear phagocytes necessary for organ homeostasis, host defense, and immunoregulation. As such, MF subtypes play a central role in regulating the pathogenesis and expression of diseases as diverse as sepsis, atherosclerosis and asthma. Infection with diverse bacteria and viruses gives rise to classically activated macrophages (CAMF), which produce pro- inflammatory cytokines (e.g., TNF, IL-12, IL-23) and nitric oxide (NO) that, together, drive potent anti-microbial functions. In contrast, allergic reactions and worm infestation stimulate the differentiation of alternatively activated macrophages (AAMF) via exposure to IL-4 and/or IL-13 that promotes allergic disease and helminth destruction. AAMF selectively express arginases (isoforms I and II) to metabolize L-arginine into polyamines and proline, implicating AAMF as regulators of cellular proliferation and fibrosis during the wound healing response and effector cells of T helper type 2 (TH2) immunity. Schistosoma mansoni is a major human pathogen affecting 108 people worldwide that causes fibrotic granulomatous inflammation in multiple organ systems. Schistosoma pathogenesis is remarkably similar in humans and mice, both of which require TH2 responses for survival during the acute phase of infection. We have generated several genetic models that facilitate careful mechanistic dissection of the cell-lineage specific importance of TH2 associated gene expression. Notably, we have demonstrated that IL-4/IL-13-driven MF activity prevents lethal immunopathology in mouse schistosomiasis. We now have evidence that arginase itself is responsible for blocking IL-12/23p40 induction, driving collagen production, and limiting severe inflammation of liver and intestine. Together, these data strongly support our inter-related central hypotheses: (1) AAMF are necessary and sufficient to prevent lethal immunopathology in mice infected with Schistosoma mansoni; and (2) The mechanism of such protection is dependent on arginase production. We will use our genetic models to address these hypotheses in the following aims: Aim 1 will test the hypothesis that AAMF production of Arginases I and/or II prevents lethal immunopathology in S. mansoni- infected mice; Aim 2 will test the hypothesis that MF IL-4R1 expression is necessary and sufficient for host protection against lethal immunopathology during Schistosomiasis; Aim 3 will test the hypothesis that lethal inflammation in S. mansoni-infected mice is driven by CAMF. These hypotheses have broad implications that go beyond MF function during worm infection because MF are fundamental components of a wide range of chronic human inflammatory diseases. A greater mechanistic understanding of the molecular regulation of MF effector function should allow for the design of novel therapeutic approaches to such inflammatory diseases.Macrophages (MF) are a heterogeneous population of immune cells that play a central role in determining the outcome of many diseases, including infections (e.g., sepsis), autoinflammatory diseases (e.g., atherosclerosis), allergic diseases (e.g. asthma) and cancer. This proposal will use a mouse model of inflammation to test our hypothesis that interleukins 4 and 13 are essential for the differentiation of a specific functional population of MF (alternatively activated macrophages [AAMF]) that are both necessary and sufficient for suppression of lethal immunopathology by producing a specific enzyme of L-arginine metabolism called arginase. A greater mechanistic understanding of macrophage effector function on a molecular level of should allow for the design of novel therapeutic approaches to the myriad diseases whose expression is controlled by MF.